摘要 |
A molecular model of pokeweed antiviral protein (PAP)-RNA interactions was used to rationally engineer FLP-102 (151AA152) and FLP-105 (191AG192) as nontoxic PAP proteins with potent anti-HIV activity. FLP-102 and FLP-105 hav e been produced in E. coli and tested both in vitro as well as in vivo. These proteins depurinate HIV-1 RNA much better than ribosomal RNA and are more potent anti-HIV agents than native PAP or recombinant wild-type PAP. They ar e substantially less toxic than native PAP in BALB/c mice and exhibit potent i n vivo activity against genotypically and phenotypically NRTI-resistant HIV-1 in a surrogate Hu-PBL-SLID mouse model of human AIDS. Rationally engineered nontoxic recombinant PAP proteins such as FLP-102 and FLP-105 may provide th e basis for effective salvage therapies for patients harboring highly drug resistant strains of HIV-1. The documented in vitro potency of FLP-102 and F LP- 105, their in vivo antiretroviral activity in HIV-infected Hu-PBL SCID mice, and their favorable toxicity profile in BALB/c mice warrant the further development of these promising new biotherapeutic agents.
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